TY - JOUR
T1 - Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases
AU - Leoni, Valerio
AU - Gatta, Valentina
AU - Palladini, Arianna
AU - Nicoletti, Giordano
AU - Ranieri, Dario
AU - Dall'Ora, Massimiliano
AU - Grosso, Valentina
AU - Rossi, Martina
AU - Alviano, Francesco
AU - Bonsi, Laura
AU - Nanni, Patrizia
AU - Lollini, Pier Luigi
AU - Campadelli-Fiume, Gabriella
PY - 2015
Y1 - 2015
N2 - Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.
AB - Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.
KW - Mesenchymal stem cells
KW - Metastases
KW - Oncolytic herpes simplex virus
KW - Systemic delivery
KW - Viral retargeting
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UR - http://www.scopus.com/inward/citedby.url?scp=84946593779&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.5793
DO - 10.18632/oncotarget.5793
M3 - Article
AN - SCOPUS:84946593779
VL - 6
SP - 34774
EP - 34787
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 33
ER -